Apilimod, also referred to as STA-5326, hereinafter “apilimod”, is recognized as a potent transcriptional inhibitor of IL-12 and IL-23. See e.g., Wada et al. Blood 109 (2007): 1156-1164. IL-12 and IL-23 are inflammatory cytokines normally produced by immune cells, such as B-cells and macrophages, in response to antigenic stimulation. Autoimmune disorders and other disorders characterized by chronic inflammation are characterized in part by inappropriate production of these cytokines. In immune cells, the selective inhibition of IL-12/IL-23 transcription by apilimod was recently shown to be mediated by apilimod's direct binding to phosphatidylinositol-3-phosphate 5-kinase (PIKfyve). See, e.g., Cai et al. Chemistry and Biol. 20 (2013):912-921. PIKfyve plays a role in Toll-like receptor signaling, which is important in innate immunity.
Some neurodegenerative diseases result in the accumulation of protein aggregates or other intermediates of cellular catabolism that may lead to neural toxicity and degeneration.
Glutamate, also referred to as glutamic acid, is the main excitatory neurotransmitter in humans. It is also a substrate in the synthesis of the main inhibitory neurotransmitter, GABA (γ-Aminobutyric acid), which regulates neuronal excitability.
Glutamate transporters are a family of neurotransmitter transporter proteins that move glutamate across neural cell membranes. Glutamate transporters include two main classes, the excitatory amino acid transporters and the vesicular glutamate transporters. The amino acid transporters remove glutamate from the synaptic cleft by stimulating reuptake into neural cells. The vesicular transporters move glutamate intracellularly from the cell cytoplasm into synaptic vesicles.
Glutamate excitotoxicity refers to a pathological process by which neural cells are damaged or destroyed by excessive glutamate stimulation. High levels of glutamate cause the over-stimulation of glutamate receptors such as the N-methyl-D-aspartate (NMDA) and AMPA receptors, setting in motion the pathological activation of various intracellular enzymes that results in damage to cellular structures including the cytoskeleton, membranes, and even DNA.
Glutamate excitotoxicity is implicated in various neurological diseases and disorders including spinal cord injury, stroke, and traumatic brain injury, as well as in certain neurodegenerative diseases of the central nervous system including multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, alcoholism or alcohol withdrawal and Huntington's disease.